This Report involves work collected under protocol 04-M-0222 (NCT00088699). Our research suggests that the glutamatergic system is involved in the mechanism of action of antidepressants. We found that the non-competitive NMDA antagonist (ketamine) resulted in rapid, robust and relatively sustained antidepressant and antisuicidal effects. Response with ketamine occurred within 2 hours and lasted approximately 1 week. Comparable response rates with existing treatments occur at 6-8 weeks instead of hours. Study 1: (Biomarkers of rapid response in major depressive disorder). OBJECTIVE: To examine what the neural correlates are of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. We found robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Study 2: (Biomarkers of rapid response in bipolar depression). OBJECTIVE: To examine what the neural correlates are of rapid antidepressant response to the NMDA antagonist ketamine in subjects with major depressive disorder. We found robust and rapid antidepressant effects resulted from a single intravenous dose of an N-methyl-D-aspartate antagonist; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week. Aims are 1) to examine the antisuicidal effects of ketamine, and 2) to examine correlates of antidepressant response to ketamine in both major depressive disorder and bipolar disorder and include: clinical (e.g., family history), imaging (positron emission tomography PET, magnetic resonance imaging/spectroscopy), electrophysiological (magnetoencephalography MEG, electroencephalography EEG), neuropsychological, and biochemical (e.g., genetics, microRNA, BDNF, metabolomics). Results in the past year: 1) Riluzole, a glutamatergic modulator used for the treatment for amyotrophic lateral sclerosis (ALS) likely lacks antidepressant efficacy in ketamine non-responders. Subjects who were treated with ketamine non-responders were randomized to riluzole or placebo. There was no difference in response rates over the course of 4 weeks. 2) D-serine plasma concentration is a potential biomarker of (R,S)-ketamine antidepressant response in subjects with treatment-resistant depression. Baseline D-serine plasma concentrations were significantly lower in ketamine responders (3.02&#8201;&#8201;0.21 &#956;M) than in ketamine non-responders (4.68&#8201;&#8201;0.81 &#956;M), p&#8201;<&#8201;0.001. A significant relationship between baseline D-serine plasma concentrations and percent change in depression scores at 230 minutes was found. Baseline D-serine explaining 60 % of the variance in (R,S)-ketamine response. Measurement of blood D-serine could serve as a biomarker predicting rapid antidepressant response. 3) Clinical predictors of ketamine response in treatment-resistant major depression. We found that higher body mass index correlated with greater improvement in depression scores at 230 minutes (P = .004) and at day 1 (P = .001), but not at day 7 (P = .10). Family history of an alcohol use disorder in a first-degree relative was associated with greater improvement in depressive symptoms at day 1 (P = .014) and day 7 (P < .001). No prior history of suicide attempt(s) was associated with greater improvement only at day 7 (standardized &#946; = 0.28, P = .01). The overall statistical model explained 13%, 23%, and 36% of depression scores percent change variance at 230 minutes, day 1, and day 7, respectively. 4) A pilot study of plasma metabolomic patterns for patients treated with ketamine for bipolar depression. We found evidence of a response-related difference in mitochondrial networks. The metabolomic patterns were significantly different between the patients maintained on lithium and those maintained on valproate, irrespective of response to ketamine. In the patients maintained on lithium, 18 biomarkers were identified. In responders, lysophosphatidylethanolamines (4) and lysophosphatidylcholines (9) were increased relative to non-responders. 5) Dissociative side effects of ketamine mediate its antidepressants effects. We would a significant correlation between increased dissociative side effects at 40 min and percent improvement with ketamine in depressive symptoms at 230min. 6) Ketamine treatment in patients with treatment-resistant depression was not associated with greater risk of switches into mania or dissociative side effects in those subjects with a history of trauma or post-traumatic stress disorder. 7) Ketamine regulates the presynaptic release machinery in the hippocampus. A large reduction in the accumulation of SNARE complexes was observed in hippocampal synaptic membranes after 1, 2 and 4 h of ketamine administration. In parallel, we found a selective reduction in the expression of the synaptic vesicle protein synaptotagmin I and an increase in the levels of synapsin I in hippocampal synaptosomes suggesting a mechanism by which ketamine reduces SNARE complex formation, in part, by regulating the number of synaptic vesicles in the nerve terminals. Moreover, ketamine reduced Thr(286)-phosphorylated &#945;CaMKII and its interaction with syntaxin 1A, which identifies CaMKII as a potential target for second messenger-mediated actions of ketamine.